Neural Effects of Sustained Oxytocin Treatment in Children with Autism

描述(由申请人提供)：严重的社交缺陷是自闭症谱系障碍(ASD)的显著特征。催产素在动物和人类的社会行为中起着重要的作用，最近已成为治疗ASD的靶向社交障碍的候选药物。然而，人们对催产素影响人类特别是自闭症患者社会行为的神经机制知之甚少。本项目旨在调查催产素治疗对自闭症儿童潜在社会损害的神经系统的影响。我们正在参与美国国立卫生研究院ACE网络赠款，以进行一项决定性的随机、双盲、安慰剂对照的临床试验，该试验旨在持续鼻腔内注射催产素治疗ASD儿童的互惠社会行为。这是一个独特的机会，可以利用现有的基础设施，使我们能够提供有关自闭症催产素治疗反应的神经机制的重要信息。这个项目的具体目标是检查：1)催产素如何影响社会信息处理的基本方面的神经回路--即‘镜像神经元’系统和社会奖励；2)这些回路中的活动在多大程度上预测或 与治疗反应相关。中心假设是，催产素治疗将增强这些“社交大脑”系统的活动，关键脑区(例如，额叶下回、腹侧纹状体、杏仁核和内侧前额叶皮质的盖部)的增加将与社会行为的临床改善相关。我们将使用先前验证的功能磁共振成像范式来检查参与网络试验的ASD儿童在使用催产素和安慰剂治疗前后脑活动的差异。这项拟议研究的基本原理是，更好地了解催产素影响的神经系统，将为开发针对这些网络的新药理学策略铺平道路，无论这些网络是“社会大脑”还是补偿回路。这种方法的创新之处在于，它使用了fMRI任务，这些任务利用已知的自闭症患者功能失调的电路，与社会症状的严重程度相关， 并与催产素的假想机制有直接联系。这项拟议的项目意义重大，因为它将提供有关催产素治疗儿童自闭症机制的重要信息，并为最终开发个性化治疗方法提供科学依据。在ASD样本中，越来越多的关于催产素影响的神经结构的知识有望帮助刺激新策略的发展，以增加受影响网络的激活。这项研究还有望帮助确定治疗反应的神经预测因素和相关性，这可能会支持生物标记物的开发，从而支持治疗的个性化--这是一个被广泛认为对该领域至关重要的目标。

DESCRIPTION (provided by applicant): Striking deficits in social interaction are hallmark features of autism spectrum disorders (ASD). Oxytocin plays an important role in social behavior in animals and humans and has recently emerged as a promising candidate for targeting social impairment in ASD. However, little is known about the neural mechanisms by which oxytocin influences social behavior in humans in general and ASD in particular. This project aims to investigate the impact of oxytocin treatment on the neural systems underlying social impairments in children with ASD. We are participating in an NIH ACE network grant to conduct a definitive randomized, double-blind, placebo-controlled clinical trial of sustained intranasal oxytocin treatment on reciprocal social behaviors in children with ASD. This presents a unique opportunity to take advantage of existing infrastructure that will enable us to provide important information on the neural mechanisms underlying oxytocin treatment response in autism. The specific aims of this project are to examine: 1) how oxytocin impacts the neural circuitry underlying fundamental aspects of social information processing-namely, the 'mirror neuron' system and social reward, and 2) the extent to which activity in these circuits predicts or correlates with treatment response. The central hypothesis is that treatment with oxytocin will enhance activity in these 'social brain' systems and that increases in key brain areas (e.g., pars opercularis of the inferior frontal gyrus, ventral striatum, amygdala, and medial prefrontal cortex will correlate with clinical improvement in social behavior. We will use previously validated fMRI paradigms to examine differences in brain activity before and after treatment with oxytocin and placebo in children with ASD participating in the network trial. The rationale for the proposed research is that a better understanding of the neural systems impacted by oxytocin will pave the road for developing new pharmacological strategies for targeting these networks, whether they are "social brain" or compensatory circuits. The approach is innovative in its use of fMRI tasks that tap circuitry known to be dysfunctional in autism, correlate with severity of social symptoms, and have a direct link to a hypothesized mechanism of oxytocin. The proposed project is significant because it will yield important information on the therapeutic mechanism of oxytocin in children with ASD, and offer a scientific basis on which to ultimately develop individualized approaches to treatment. Increasing knowledge about the neural architecture impacted by oxytocin in an ASD sample is expected to help stimulate the development of novel strategies for increasing activation in affected networks. This study is also expected to help identify neural predictors and correlates of treatment response, which will likely support the development of biomarkers, and thus, personalization of treatments-a target widely acknowledged as critically important for the field.